Among the organisms commonly associated with fungal infections in mammals are Candida species. Candida species, in particular Candida albicans and Candida tropicalis, are commonly found in the oral cavity and intestinal tract of humans. In healthy individuals, Candida species are generally harmless. However, when the immune system of the host is impaired, for example, in neonates, the elderly, burn patients, individuals with AIDS and cancer patients undergoing chemotherapy, Candida species can become pathogenic.
Superficial infections caused by Candida species include oral thrush, denture stomatitis, vulvovaginitis, balanitis, cutaneous candidosis, onychia, paronychia and chronic mucocutaneous candidosis. Systemic infections caused by Candida species include Candida septicemia, renal candidosis, Candida endocarditis, esophageal candidosis, bronchial candidosis and Candida endophthalmitis. Diabetics, denture wearers and AIDS patients are particularly susceptible to Candida species infections.
Agents currently used to treat Candida species infections are amphotericin B, nystatin, flucytosine, ketoconazole, miconazole, clotrimazole, fluconazole and itraconazole and the like. Many of these agents have serious side effects.
It is well-known that Candida species produce an acid protease which is believed to be a virulence factor. Strains of Candida albicans which are deficient in or lack this acid protease have reduced virulence when compared to acid protease positive strains. It has been suggested that an inhibitor of the Candida acid protease would be a useful therapeutic agent (Ray, et al., Infection and Immunity 58 508 (1990); Tsuobi, et al., J. Invest. Dermatol. 85 438 (1985); Ruchel, et al., Zbl. Bakt. 273 391 (1990); Zotter, et al., Dermatol. Mon.schr. 176 189 (1990)).
Pepstatin A and chymostatin are known to inhibit Candida acid protease. However, these compounds would not be suitable therapeutics because they are non-specific and are not very potent inhibitors of the enzyme. Therefore, there is a need for agents which are potent and selective inhibitors of Candida acid protease.